FDA approves AceLink’s AL1211 Phase 2 trial for Fabry disease

Experimental substrate reduction therapy to be tested in male patients

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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AceLink Therapeutics’ Phase 2 trial testing AL1211 as a treatment for Fabry disease has been cleared to launch by the U.S. Food and Drug Administration (FDA).

The trial will evaluate AL1211’s safety and pharmacological properties in men diagnosed with classic Fabry disease who are willing to switch from their standard enzyme replacement therapy.

“Given the encouraging results from our Phase 1 study, we look forward to further investigating AL1211 in our Phase 2 program as we strive to bring a novel treatment option to those patients who need it most,” Pedro Huertas, MD, PhD, chief medical officer at AceLink, said in a press release.

“Our clinical team has diligently prepared for this moment and we are eager to enroll patients as rapidly as possible,” he added.

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Substrate reduction therapy designed to prevent generation of fatty molecules

Fabry disease is caused by genetic mutations in the GLA gene, which provides instructions to produce the alpha-galactosidase A (GalA) enzyme, responsible for the breakdown of fatty molecules, particularly globotriaosylceramide (Gb3). This leads to the accumulation of Gb3 in small blood vessels and tissues, causing organ damage.

Standard enzyme replacement therapies work to provide a functional version of the missing enzyme, restoring the body’s ability to break down Gb3. In contrast, AL1211, previously referred to as AL01211, is a substrate reduction therapy that acts by preventing the generation of fatty molecules like Gb3.

It does so by inhibiting glucosylceramide synthase (GCS), an enzyme that facilitates the first step in the production of glycosphingolipids, a diverse group of biologically active fatty molecules that includes Gb3. By blocking this enzyme, AL1211 works to reduce Gb3 toxic accumulation and related inflammation and improve organ function, ultimately slowing disease progression.

The therapy demonstrates high potency against GCS as well as other favorable pharmacological properties. These properties are expected to enable convenient once-daily oral dosing, offering a more convenient treatment approach compared to enzyme replacement therapy, according to the company.

Given the encouraging results from our Phase 1 study, we look forward to further investigating AL1211 in our Phase 2 program as we strive to bring a novel treatment option to those patients who need it most.

AL1211 is unable to cross the blood-brain barrier, meaning it will not enter the brain and the spinal cord (collectively known as the central nervous system). This maximizes the treatment effect on targeted organs while reducing the potential of negative effects on the central nervous system. The blood-brain barrier is a semipermeable membrane that protects the brain and spinal cord from the external environment.

Phase 1 trials conducted in Australia (NCT04908462) and China (ChiCTR2200061431) evaluated single ascending dosing and multiple ascending dosing of AL1211. Healthy volunteers received oral administration of AL1211 either as a single dose of up to 60 mg or multiple doses of up to 30 mg once daily for 14 days.

The therapy was found to be safe and generally well-tolerated, with no serious adverse effects at any dose tested, according to the company.

Moreover, a dose-dependent increase in AL1211 blood levels correlated with a greater reduction in blood glucosylceramide, a marker of GCS inhibition. Specifically, the 30 mg dose reduced glucosylceramide levels by 78%, with Gb3 levels also significantly reduced.

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AL1211 granted FDA’s orphan drug designation in September 2022

“FDA clearance for AL1211 marks an important clinical milestone for AceLink,” said Jerry Shen, PhD, CEO and founder of the company.

“We are committed to providing a differentiated oral therapy for patients with Fabry Disease and Type 1 Gaucher Disease, who are desperately in need of a more convenient alternative to enzyme replacement therapy, and ultimately a better quality of life,” Shen added.

The therapy was granted orphan drug designation by the FDA in September 2022. The designation is provided to investigational treatments that have the potential to improve care for rare diseases, affecting fewer than 200,000 people in the U.S.

It also provides AceLink, as the therapy’s developer, certain incentives such as tax credits, fee waivers, and seven years of market exclusivity if the treatment is approved.